High selectivity of cleavage and general applicability to all commonly occurring amino acids are important criteria in choosing useful combinations of main chain and side chain protecting groups in peptide synthesis. The most selective procedure available to date has been catalytic hydrogenolysis of N.sup..alpha.-benzyloxycarbonyl (Z) groups in peptides whose side chain functions have been protected by t-butyl ester, t-butyl ether and/or t-butyloxycarbonyl (Boc) groups which completely resist hydrogenolysis. However, this excellent system has not been generally applicable since catalytic hydrogenolysis failed with cysteine or methionine containing peptides due to catalyst poisoning.
There have been attempts to overcome this restriction by resorting to various expedients. Examples of such expedients include the addition of a tertiary base (Acta Chim. Acad. Sci. Hung., 45, 15 (1965); 50, 339 (1966)) or of boron trifluoride etherate (Chem. Pharm. Bull., 16, 1342 (1968), to the hydrogenolysis reaction medium. Another suggested technique involves the use of the N.sup..alpha.-1,1-dimethyl-2-propynyloxycarbonyl group (J. Amer. Chem. Soc., 93, 3302 (1971)) which may be hydrogenolized with partially poisoned catalysts. In no case, however, has it been possible to achieve the desired levels of selective deblocking and high end product yields with these techniques.
It is further known in the art to employ liquid ammonia as a solvent for many amino acid derivatives and protected peptides some of which are not readily soluble in other solvents. See, for example, the papers by du Vigneaud et al. in J. Amer. Chem. Soc. 52, 4500 (1930) and 75, 3879 (1953).